Rare variants in FANCA induce premature ovarian insufficiency

• DOI: 10.1007/s00439-019-02059-9
• Publication Date: 2019-09-18T07:02:46Z
• Authors: Xi Yang; Xiaojin Zhang; Jiao Jiao; Feng Zhang; Yuncheng Pan; Qiqi Wang; Qing Chen; Baozhu Cai; Shuyan Tang; Zixue Zhou; Siyuan Chen; Hao Yin; Wei Fu; Yang Luo; Da Li; Guoqing Li; Lingyue Shang; Jialing Yang; Li Jin; Qinghua Shi; Yanhua Wu
• Keywords: FANCA; Premature ovarian insufficiency; FANCD2

Abstract Premature ovarian insufficiency (POI) is a major cause of reduced female fertility and affects approximately 1% women under 40 years age. Recent advances emphasize the genetic heterogeneity POI. Fanconi anemia (FA) genes, traditionally known for their essential roles in DNA repair cytogenetic instability, have been demonstrated to be involved meiosis germ cell development. Here, we conducted whole-exome sequencing (WES) 50 Han Chinese patients with Rare missense variants were identified FANCA ( complementation group A ): c.1772G > (p.R591Q) c.3887A G (p.E1296G). Both are heterozygous very rare human population. In vitro functional studies further that these two exhibited protein expression levels compared wild type, suggesting partial loss function. Moreover, mono-ubiquitination FANCD2 upon mitomycin C stimulation significantly cells overexpressing variants. Furthermore, loss-of-function mutation Fanca was generated C57BL/6 mice vivo assay. Consistently, mutated + / − ) showed declined numbers follicles aging when wild-type mice. Collectively, our results suggest pathogenic implicated non-syndromic POI women, provide new insights into molecular mechanisms highlight contribution subfertility.